The overall goal of this proposal is to use multiple preexisting NIH-funded data sources to adapt, apply and refine novel analytic epidemiologic methods to characterize the relation, and estimate the impact, of alcohol intake on risk of infection with Human Immunodeficiency Virus (HIV). The relation between alcohol intake and HIV seroconversion remains poorly understood >2 decades after the onset of the HIV epidemic. The aims of the present proposal will be undertaken using three prospective cohort studies, which are US national treasures: the AIDS Link to Intravenous Experience (ALIVE) cohort study, the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS). We will adapt, apply and refine marginal structural models to these complex longitudinal data and characterize the relation between alcohol intake and HIV seroconversion;we will quantify the impact of specified changes in alcohol intake and risk of HIV infection (e.g., complete cessation, halving of grams/day, cessation of binging). Specifically, we aim to: 1-determine the (1a) propensity of alcohol intake and patterns based on measured behavioral, demographic and biomedical factors, and (1b) explore the relation between broad (i.e., frequency and intensity) and more nuanced (i.e., plus type and size) alcohol intake assessments;2- estimate the total effect (i.e., direct and indirect) of alcohol intake and patterns on risk of HIV seroconversion, explore whether the total effect is modified by age, sex or calendar year, and quantify the uncertainty due to measurement error, unmeasured confounding, and selection bias;3-estimate the joint (i.e., modifying) effect of alcohol intake and patterns and illicit or recreational prescription drug use on risk of HIV seroconversion;and 4- explore the indirect effects of alcohol intake and patterns on risk of HIV seroconversion, mediated through subsequent (a) risky sexual behavior or (b) measured markers of immune function. Randomization of individuals to specified levels of many exposures important to the public's health (e.g., alcohol intake) is both unethical and impractical. Issues of time-varying confounding, measurement error, emigrative selection bias (due to follow up loss), mediation by time-varying risk behaviors/immune function, and effect modification all apply in force to observational data on alcohol intake and HIV seroconversion and are addressed in this proposal. The proposed research is directly relevant to real, long-standing challenges in biomedical and public health research. Specifically, research findings will provide necessary evidence for the development of targeted interventions and public health messages in persons at-risk for HIV. In summary, the present proposal describes a unique opportunity and a significant, innovative and cost-effective initiative to comprehensively examine, apply and refine start-of-the-art analytic methods in the context of an important scientific field of inquiry. PUBLIC HEALTH RELEVANCE: The proposed research will be directly relevant to real, long-standing challenges in biomedical and public health research in two ways. First, it will provide required clarity in understanding the relation between alcohol intake and Human Immunodeficiency Virus infection. Second, it will provide innovations and detailed worked examples in quantitative methods for complex observational data analysis.